Transendocytosis is impaired in CADASIL-mutant NOTCH3

► We examined the degradation of the NOTCH3 extracellular domain (N3ECD). ► The wild N3ECD was degraded more rapidly than mutant when co-cultured with ligand. ► The degradation of mutant N3ECD on the cell surface was disturbed. ► The impaired transendocytosis of mutant N3ECD into the ligand cells was assumed. ► The mutant N3ECD on the cell surface may contribute to the pathogenesis of CADASIL.